Multiple myeloma (MM) is a bone cancer characterized by an accumulation of tumor cells in the bone marrow of patients. MM remains incurable despite large numbers of chemotherapy drugs available for patients. The major problem in the failure to cure MM patients is that patients will become resistant to all clinically used MM drugs, including traditional chemotherapeutics and novel agents. Even worse, some patients exhibit initial resistance and thus never respond to chemotherapy drugs, and most, if not all, MM patients who do respond will relapse after treatment and die from the disease. There is a class of chemotherapy drugs, namely proteasome inhibitors (PIs) such as bortezomib (Btz) or car...

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Multiple myeloma (MM) is a bone cancer characterized by an accumulation of tumor cells in the bone marrow of patients. MM remains incurable despite large numbers of chemotherapy drugs available for patients. The major problem in the failure to cure MM patients is that patients will become resistant to all clinically used MM drugs, including traditional chemotherapeutics and novel agents. Even worse, some patients exhibit initial resistance and thus never respond to chemotherapy drugs, and most, if not all, MM patients who do respond will relapse after treatment and die from the disease. There is a class of chemotherapy drugs, namely proteasome inhibitors (PIs) such as bortezomib (Btz) or carfilzomib (Cfz), that are commonly used to treat patients with MM. Although these drugs have a good therapeutic efficacy, the response rate of Btz or Cfz in MM patients who have never been treated with them is only 27% or 48%, respectively. Moreover, most patients who respond well to the drugs initially become resistant when treated again after relapse. Therefore, there is a great need to develop better methods or drugs to overcome drug resistance. We recently did a high-throughput screening of 1855 FDA-approved drugs and found that all-trans retinoic acid (ATRA), a pan retinoic acid receptor (RAR) and retinoid X receptors (RXR) activator that is used to treat patients with acute promyelocytic leukemia, can overcome human MM cell resistance to Cfz or Btz. ATRA, which alone does not kill MM cells, enhances human MM cell sensitivity to Btz- or Cfz. Therefore, we believe that ATRA may be used to treat patients with MM to restore their response to Cfz or Btz. In this proposal, we will conduct a first-in-human phase IB/II clinical trial to determine the safety, tolerability, efficacy, and recommended phase II dosing of combination therapy using ATRA and Cfz to treat PI-refractory MM patients.

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